Association Analysis of PRSS1-PRSS2 and CLDN2-MORC4 Variants in Nonalcoholic Chronic Pancreatitis Using Tropical Calcific Pancreatitis as Model
Association Analysis of PRSS1-PRSS2 and CLDN2-MORC4 Variants in Nonalcoholic Chronic Pancreatitis Using Tropical Calcific Pancreatitis as Model
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DOI：
10.1097/mpa.0000000000000608
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发表时间：
2016-09-01
期刊：
影响因子：
2.9
通讯作者：
Chandak, Giriraj Ratan
中科院分区：
文献类型：
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作者：
Paliwal, Sumit;Bhaskar, Seema;Chandak, Giriraj Ratan
目的：PRSS1-PRSS2 （rs10273639）和CLDN2-MORC4 （rs12688220和rs7057398）变异与酒精相关性慢性胰腺炎（CP）的相关性已被确立，但与非酒精性CP的相关性尚不清楚。我们使用热带钙化性胰腺炎（TCP）作为模型来解决这种不一致。方法：对555例TCP患者和801例对照患者的PRSS1和CLDN2-MORC4基因型的5′-UTR进行测序，并进行相关性分析。PRSS1和CLDN2-MORC4变异以及p.Asn34Ser SPINK1和p.Leu26Val CTSB之间的基因相互作用也被评估。结果：我们观察到rs10273639/rs4726576在PRSS1-PRSS2中（比值比[OR] = 0.72; P = 3.50 × 10(-5)）和CLDN2-MORC4变异，rs12688220 （OR = 1.54; P = 1.22 × 10(-10)）和rs7057398 （OR = 1.50; P = 1.22 × 10(-10)）与TCP有显著相关性。携带p. Asn34Ser SPINK1的患者明显比携带rs4726576风险基因型的患者年轻（30.0岁vs 38.0岁，p = 0.015），携带这两种基因型的患者更年轻（22.0岁，p = 0.001）。携带p. Asn34Ser SPINK1的患者存在rs12688220风险等位基因可延迟发病年龄（32.0 vs 24.0岁；p = 0.013）。结论：我们的研究表明，PRSS1-PRSS2和CLDN2-MORC4变异与TCP以及非酒精性CP有很强的相关性。这些变异与p. Asn34Ser SPINK1相互作用，并影响TCP的发病年龄。然而，后面的结果需要在其他队列中得到验证。
Objective: Association of PRSS1-PRSS2 (rs10273639) and CLDN2-MORC4 (rs12688220 and rs7057398) variants with alcohol-related chronic pancreatitis (CP) is established but with nonalcoholic CP is unclear. We addressed this inconsistency using tropical calcific pancreatitis (TCP) as model.Methods: We sequenced 5'-UTR of PRSS1 and genotyped CLDN2-MORC4 variants in 555 patients with TCP and 801 controls and performed association analysis. Gene-gene interaction between PRSS1 and CLDN2-MORC4 variants and with p.Asn34Ser SPINK1 and p.Leu26Val CTSB was also evaluated.Results: We observed significant association of rs10273639/rs4726576 in PRSS1-PRSS2 (odds ratio[OR] = 0.72; P = 3.50 x 10(-5)) and CLDN2-MORC4 variants, rs12688220 (OR = 1.54; P = 1.22 x 10(-10)) and rs7057398 (OR = 1.50; P = 1.22 x 10(-10)) with TCP. Patients carrying p. Asn34Ser SPINK1 were significantly younger than those with rs4726576 risk genotype (30.0 vs 38.0 years; P = 0.015) and those carrying both were even younger (22.0 years; P = 0.001). Presence of risk allele at rs12688220 in patients carrying p. Asn34Ser SPINK1 delayed the age of onset (32.0 vs 24.0 years; P = 0.013).Conclusions: Our study establishes strong association of PRSS1-PRSS2 and CLDN2-MORC4 variants with TCP and thus with nonalcoholic CP. These variants independently interact with p. Asn34Ser SPINK1 and influence the age of onset in TCP. However, latter results need to be replicated in other cohorts.